Sunday, June 1, 2025
6/1/2025
Dissecting the Developmental and Epileptic Components of Encephalopathy in DEE - Project Summary/Abstract In patients with developmental and epileptic encephalopathies (DEEs), early life seizures and intellectual disability are frequently accompanied by disturbances in arousal/sleep, communication/social reciprocity, feeding and/or sensory integration. These neurobehavioral comorbidities are hypothesized to reflect a synergy of two independent but intertwined processes: (i) an inciting lesion (genetic or structural) capable of itself altering neurodevelopmental trajectories, and (ii) periods of frequent seizures, particularly early in life, that further exacerbate developmental delays. In many patients, behavioral deterioration may begin prior to seizure onset and may persist despite complete seizure control (or spontaneous remission). With whole exome sequencing, we now recognize a rapidly expanding list of genetic DEEs, which have lent to genetically informed mouse models that are critically poised to develop the urgently needed precision therapies that extend beyond seizure control. Today’s models are actively revealing novel mechanistic insights into molecular and circuit-level patho- physiology, thanks to the latest advances in genome manipulation and measurements of omics, functional connectivity and calcium imaging, as well as continued ergonomic improvements in rodent electro- encephalography. In contrast, there have been few technical and conceptual innovations within preclinical assays for neurobehavioral impairment, leaving the field reliant on behavioral batteries that may be confounded by primary disturbances in sleep/arousal, seizure recency, motor deficits and human olfactory interference. In this application, we apply the latest advances in homecage instrumentation and automated videotracking to define endpoints for DEE-related neurobehavioral impairment that are derived under experimenter-free conditions (remote behavioral telemetry). We describe a mouse model of DEE with early life seizures that displays a robust multifaceted behavioral syndrome with core features of hyperactivity and insomnia. Using this model system, this proposal tests the central hypothesis of genetic DEE, that the neurobehavioral consequences of the causative genetic lesion can be dissociated from the behavioral aftereffects of recurrent early life seizures. In Aim 1, we examine a transcription factor that is activated by seizures in the hippocampus, and which is known to shape a range of emotional and cognitive behaviors. In Aim 2, we test the importance of early life seizures by comparing behavioral and epileptic consequences of an early versus late genetic ablation. In Aim 3, we connect hyperactivity and insomnia in our mutant mice to primary disruptions in 5h ultradian rhythms of activity, and test whether pharmacological or behavioral interventions to restore ultradian rhythms exert therapeutic benefits. In the short term, these experiments will build molecular and circuit-level insights while delivering a set of novel neurobehavioral endpoints to facilitate drug discovery in DEE models. In the long term, this work develops the preclinical foundation for digital neuropsychiatry, where subjective measures of behavioral wellbeing are supplemented with continuous, in situ wearable-derived endpoints that inform clinical trials and patient care.
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